Whole genomes redefine the mutational landscape of pancreatic cancer

Nicola Waddell; Marina Pajic; Ann Marie Patch; David K. Chang; Karin S. Kassahn; Peter Bailey; Amber L. Johns; David Miller; Katia Nones; Kelly Quek; Michael C.J. Quinn; Alan J. Robertson; Muhammad Z.H. Fadlullah; Tim J.C. Bruxner; Angelika N. Christ; Ivon Harliwong; Senel Idrisoglu; Suzanne Manning; Craig Nourse; Ehsan Nourbakhsh; Shivangi Wani; Peter J. Wilson; Emma Markham; Nicole Cloonan; Matthew J. Anderson; J. Lynn Fink; Oliver Holmes; Stephen H. Kazakoff; Conrad Leonard; Felicity Newell; Barsha Poudel; Sarah Song; Darrin Taylor; Nick Waddell; Scott Wood; Qinying Xu; Jianmin Wu; Mark Pinese; Mark J. Cowley; Hong C. Lee; Marc D. Jones; Adnan M. Nagrial; Jeremy Humphris; Lorraine A. Chantrill; Venessa Chin; Angela M. Steinmann; Amanda Mawson; Emily S. Humphrey; Emily K. Colvin; Angela Chou; Christopher J. Scarlett; Andreia V. Pinho; Marc Giry-Laterriere; Ilse Rooman; Jaswinder S. Samra; James G. Kench; Jessica A. Pettitt; Neil D. Merrett; Christopher Toon; Krishna Epari; Nam Q. Nguyen; Andrew Barbour; Nikolajs Zeps; Nigel B. Jamieson; Janet S. Graham; Simone P. Niclou; Rolf Bjerkvig; Robert Grützmann; Daniela Aust; Ralph H. Hruban; Anirban Maitra; Christine A. Iacobuzio-Donahue; Christopher L. Wolfgang; Richard A. Morgan; Rita T. Lawlor; Vincenzo Corbo; Claudio Bassi; Massimo Falconi; Giuseppe Zamboni; Giampaolo Tortora; Margaret A. Tempero; Anthony J. Gill; James R. Eshleman; Christian Pilarsky; Aldo Scarpa; Elizabeth A. Musgrove; John V. Pearson; Andrew V. Biankin; Sean M. Grimmond

doi:10.1038/nature14169

Whole genomes redefine the mutational landscape of pancreatic cancer

Nicola Waddell, Marina Pajic, Ann Marie Patch, David K. Chang, Karin S. Kassahn, Peter Bailey, Amber L. Johns, David Miller, Katia Nones, Kelly Quek, Michael C.J. Quinn, Alan J. Robertson, Muhammad Z.H. Fadlullah, Tim J.C. Bruxner, Angelika N. Christ, Ivon Harliwong, Senel Idrisoglu, Suzanne Manning, Craig Nourse, Ehsan NourbakhshShivangi Wani, Peter J. Wilson, Emma Markham, Nicole Cloonan, Matthew J. Anderson, J. Lynn Fink, Oliver Holmes, Stephen H. Kazakoff, Conrad Leonard, Felicity Newell, Barsha Poudel, Sarah Song, Darrin Taylor, Nick Waddell, Scott Wood, Qinying Xu, Jianmin Wu, Mark Pinese, Mark J. Cowley, Hong C. Lee, Marc D. Jones, Adnan M. Nagrial, Jeremy Humphris, Lorraine A. Chantrill, Venessa Chin, Angela M. Steinmann, Amanda Mawson, Emily S. Humphrey, Emily K. Colvin, Angela Chou, Christopher J. Scarlett, Andreia V. Pinho, Marc Giry-Laterriere, Ilse Rooman, Jaswinder S. Samra, James G. Kench, Jessica A. Pettitt, Neil D. Merrett, Christopher Toon, Krishna Epari, Nam Q. Nguyen, Andrew Barbour, Nikolajs Zeps, Nigel B. Jamieson, Janet S. Graham, Simone P. Niclou, Rolf Bjerkvig, Robert Grützmann, Daniela Aust, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Christopher L. Wolfgang, Richard A. Morgan, Rita T. Lawlor, Vincenzo Corbo, Claudio Bassi, Massimo Falconi, Giuseppe Zamboni, Giampaolo Tortora, Margaret A. Tempero, Anthony J. Gill, James R. Eshleman, Christian Pilarsky, Aldo Scarpa, Elizabeth A. Musgrove, John V. Pearson, Andrew V. Biankin, Sean M. Grimmond

School of Medicine

Research output: Contribution to journal › Article › peer-review

1291 Scopus citations

Abstract

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

Original language	English (US)
Pages (from-to)	495-501
Number of pages	7
Journal	Nature
Volume	518
Issue number	7540
DOIs	https://doi.org/10.1038/nature14169
State	Published - Feb 26 2015

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Waddell, N., Pajic, M., Patch, A. M., Chang, D. K., Kassahn, K. S., Bailey, P., Johns, A. L., Miller, D., Nones, K., Quek, K., Quinn, M. C. J., Robertson, A. J., Fadlullah, M. Z. H., Bruxner, T. J. C., Christ, A. N., Harliwong, I., Idrisoglu, S., Manning, S., Nourse, C., ... Grimmond, S. M. (2015). Whole genomes redefine the mutational landscape of pancreatic cancer. Nature, 518(7540), 495-501. https://doi.org/10.1038/nature14169

Waddell, N, Pajic, M, Patch, AM, Chang, DK, Kassahn, KS, Bailey, P, Johns, AL, Miller, D, Nones, K, Quek, K, Quinn, MCJ, Robertson, AJ, Fadlullah, MZH, Bruxner, TJC, Christ, AN, Harliwong, I, Idrisoglu, S, Manning, S, Nourse, C, Nourbakhsh, E, Wani, S, Wilson, PJ, Markham, E, Cloonan, N, Anderson, MJ, Fink, JL, Holmes, O, Kazakoff, SH, Leonard, C, Newell, F, Poudel, B, Song, S, Taylor, D, Waddell, N, Wood, S, Xu, Q, Wu, J, Pinese, M, Cowley, MJ, Lee, HC, Jones, MD, Nagrial, AM, Humphris, J, Chantrill, LA, Chin, V, Steinmann, AM, Mawson, A, Humphrey, ES, Colvin, EK, Chou, A, Scarlett, CJ, Pinho, AV, Giry-Laterriere, M, Rooman, I, Samra, JS, Kench, JG, Pettitt, JA, Merrett, ND, Toon, C, Epari, K, Nguyen, NQ, Barbour, A, Zeps, N, Jamieson, NB, Graham, JS, Niclou, SP, Bjerkvig, R, Grützmann, R, Aust, D, Hruban, RH, Maitra, A, Iacobuzio-Donahue, CA, Wolfgang, CL, Morgan, RA, Lawlor, RT, Corbo, V, Bassi, C, Falconi, M, Zamboni, G, Tortora, G, Tempero, MA, Gill, AJ, Eshleman, JR, Pilarsky, C, Scarpa, A, Musgrove, EA, Pearson, JV, Biankin, AV & Grimmond, SM 2015, 'Whole genomes redefine the mutational landscape of pancreatic cancer', Nature, vol. 518, no. 7540, pp. 495-501. https://doi.org/10.1038/nature14169

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title = "Whole genomes redefine the mutational landscape of pancreatic cancer",

abstract = "Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.",

author = "Nicola Waddell and Marina Pajic and Patch, {Ann Marie} and Chang, {David K.} and Kassahn, {Karin S.} and Peter Bailey and Johns, {Amber L.} and David Miller and Katia Nones and Kelly Quek and Quinn, {Michael C.J.} and Robertson, {Alan J.} and Fadlullah, {Muhammad Z.H.} and Bruxner, {Tim J.C.} and Christ, {Angelika N.} and Ivon Harliwong and Senel Idrisoglu and Suzanne Manning and Craig Nourse and Ehsan Nourbakhsh and Shivangi Wani and Wilson, {Peter J.} and Emma Markham and Nicole Cloonan and Anderson, {Matthew J.} and Fink, {J. Lynn} and Oliver Holmes and Kazakoff, {Stephen H.} and Conrad Leonard and Felicity Newell and Barsha Poudel and Sarah Song and Darrin Taylor and Nick Waddell and Scott Wood and Qinying Xu and Jianmin Wu and Mark Pinese and Cowley, {Mark J.} and Lee, {Hong C.} and Jones, {Marc D.} and Nagrial, {Adnan M.} and Jeremy Humphris and Chantrill, {Lorraine A.} and Venessa Chin and Steinmann, {Angela M.} and Amanda Mawson and Humphrey, {Emily S.} and Colvin, {Emily K.} and Angela Chou and Scarlett, {Christopher J.} and Pinho, {Andreia V.} and Marc Giry-Laterriere and Ilse Rooman and Samra, {Jaswinder S.} and Kench, {James G.} and Pettitt, {Jessica A.} and Merrett, {Neil D.} and Christopher Toon and Krishna Epari and Nguyen, {Nam Q.} and Andrew Barbour and Nikolajs Zeps and Jamieson, {Nigel B.} and Graham, {Janet S.} and Niclou, {Simone P.} and Rolf Bjerkvig and Robert Gr{\"u}tzmann and Daniela Aust and Hruban, {Ralph H.} and Anirban Maitra and Iacobuzio-Donahue, {Christine A.} and Wolfgang, {Christopher L.} and Morgan, {Richard A.} and Lawlor, {Rita T.} and Vincenzo Corbo and Claudio Bassi and Massimo Falconi and Giuseppe Zamboni and Giampaolo Tortora and Tempero, {Margaret A.} and Gill, {Anthony J.} and Eshleman, {James R.} and Christian Pilarsky and Aldo Scarpa and Musgrove, {Elizabeth A.} and Pearson, {John V.} and Biankin, {Andrew V.} and Grimmond, {Sean M.}",

year = "2015",

month = feb,

day = "26",

doi = "10.1038/nature14169",

language = "English (US)",

volume = "518",

pages = "495--501",

journal = "Nature",

issn = "0028-0836",

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T1 - Whole genomes redefine the mutational landscape of pancreatic cancer

AU - Waddell, Nicola

AU - Pajic, Marina

AU - Patch, Ann Marie

AU - Chang, David K.

AU - Kassahn, Karin S.

AU - Bailey, Peter

AU - Johns, Amber L.

AU - Miller, David

AU - Nones, Katia

AU - Quek, Kelly

AU - Quinn, Michael C.J.

AU - Robertson, Alan J.

AU - Fadlullah, Muhammad Z.H.

AU - Bruxner, Tim J.C.

AU - Christ, Angelika N.

AU - Harliwong, Ivon

AU - Idrisoglu, Senel

AU - Manning, Suzanne

AU - Nourse, Craig

AU - Nourbakhsh, Ehsan

AU - Wani, Shivangi

AU - Wilson, Peter J.

AU - Markham, Emma

AU - Cloonan, Nicole

AU - Anderson, Matthew J.

AU - Fink, J. Lynn

AU - Holmes, Oliver

AU - Kazakoff, Stephen H.

AU - Leonard, Conrad

AU - Newell, Felicity

AU - Poudel, Barsha

AU - Song, Sarah

AU - Taylor, Darrin

AU - Waddell, Nick

AU - Wood, Scott

AU - Xu, Qinying

AU - Wu, Jianmin

AU - Pinese, Mark

AU - Cowley, Mark J.

AU - Lee, Hong C.

AU - Jones, Marc D.

AU - Nagrial, Adnan M.

AU - Humphris, Jeremy

AU - Chantrill, Lorraine A.

AU - Chin, Venessa

AU - Steinmann, Angela M.

AU - Mawson, Amanda

AU - Humphrey, Emily S.

AU - Colvin, Emily K.

AU - Chou, Angela

AU - Scarlett, Christopher J.

AU - Pinho, Andreia V.

AU - Giry-Laterriere, Marc

AU - Rooman, Ilse

AU - Samra, Jaswinder S.

AU - Kench, James G.

AU - Pettitt, Jessica A.

AU - Merrett, Neil D.

AU - Toon, Christopher

AU - Epari, Krishna

AU - Nguyen, Nam Q.

AU - Barbour, Andrew

AU - Zeps, Nikolajs

AU - Jamieson, Nigel B.

AU - Graham, Janet S.

AU - Niclou, Simone P.

AU - Bjerkvig, Rolf

AU - Grützmann, Robert

AU - Aust, Daniela

AU - Hruban, Ralph H.

AU - Maitra, Anirban

AU - Iacobuzio-Donahue, Christine A.

AU - Wolfgang, Christopher L.

AU - Morgan, Richard A.

AU - Lawlor, Rita T.

AU - Corbo, Vincenzo

AU - Bassi, Claudio

AU - Falconi, Massimo

AU - Zamboni, Giuseppe

AU - Tortora, Giampaolo

AU - Tempero, Margaret A.

AU - Gill, Anthony J.

AU - Eshleman, James R.

AU - Pilarsky, Christian

AU - Scarpa, Aldo

AU - Musgrove, Elizabeth A.

AU - Pearson, John V.

AU - Biankin, Andrew V.

AU - Grimmond, Sean M.

PY - 2015/2/26

Y1 - 2015/2/26

N2 - Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

AB - Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

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JO - Nature

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Whole genomes redefine the mutational landscape of pancreatic cancer

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